Different neuropeptide-containing nerve fibers were investigated to clarify their role in the pathogenesis of Crohn's disease (CD) using immunohisto- and immunocytochemical techniques. Specimens were obtained from patients with CD from grossly affected colonic regions, from biopsies obtained from patients with CD treated with mesalazine and from control individuals. Quantitative analysis was made for the changes of the number of nerve terminals and their vesicle contents. The distribution pattern of all immunoreactive (IR) nerve fibers was similar both in the control and in the surgical specimens as well as in the biopsies obtained. The number of the synapses, the IR nerve fibers and their vesicle content were markedly decreased in the grossly affected colonic regions. Some degenerated axons were found in close proximity to the plasma cells. Immunocytochemistry demonstrated that substance P, vasoactive intestinal polypeptide and somatostatin IR nerve fibers were in direct contact with the plasma cells, lymphocytes and other immunocompetent cells. The gap between the membranes of immunoreactive nerve terminals and immunocompetent cells was 20–200 nm, in a few cases even less. In the mesalazine-treated group the number of the IR nerve terminals as well as their vesicle content was increased. These results suggest that changes in the number of different neuropeptide-containing nerve terminals and their content might alter the neuroimmunological processes, because these peptides are known to be immunoregulators.